Peeparation of 2-keto aldonic acids from aldonic acids



mama 1; so, 1946 UNITED-STATES PATENT orrlcc mm v non ALDONIO ACIDS N. Y., andl'eter crate N. '!.,a

corporation at New Janey No Drawing. Application December 24, 1988, Serial No. 247,644

'IGIalme. (circa-:5)

The object or this invention is the preparation of 2-keto aldonic acids from the corresponding aldonic acids by a catalytic chemical oxidation.

It is knownto prepare 2-keto gluconic acid I from gluconic acid by means of an oxidative i'ermentation (Bernhauer and Giirlich, Biochem. Z. 280:387-14 (1935) However, this appears to be a specific reaction and there is no evidence that it is applicable toother aldonic 1. Since the molecule of an aldonic acid contains many points of attack; it is obvious that chemical oxidizing agents must be highly selective in their action iithey are to dehydrogenate only. the second carbon atom.

.13 We have now found that chlorates in the presence oi'- vanadium as catalyst produce the desired result. When this oxidizing combination acts upon free aldonic acids-or rather upon their equilibrium mixtures of acid and lactone-the Q recovery of 2-keto acid is relatively small. However, substantially better yields are obtained when soluble aldonates are treated in a mildly acid medium. Suitable acidifying a ents are small amounts of mineral acids, or organic acids which El are stable toward chlorates in the presence of vanadium. We prefer to adjust the acidity to a pH between 3 and 4, and it is desirable to maintain it within this range by the use of sodium acetate or sodium phosphate butters.

8 The amount of vanadium which is added is not critical. About 2% or the weight 01' aldonate present is an adequate proportion. While this reaction proceeds well at room temperature, the rate or reaction is increased by raising the temso pera'ture, although it is not desirable to heat the simple method of isolating the'salts oi! the 2-keto acids from the vanadium-free solution isby tractiomal precipitation by alcohol. The 2-keto acid 45 formed may be determined by means of al'ehling's solution which has been standardised against the particular fl-keto acid.

The following aldonates have been oxidised by the new process: gluconates, idonates, gmonates, 5o galactonates, arabonate.

trample! The oxidation otsodium-d-glueonatetosodium 109 grams of sodium gluconate and 18 grams of sodium-chlorate are dissolved in about 500 cc. of water. To this solution 50 cc. of acetic acid and about 4 grams of vanadium pentoxide are added. The mixture is stirred for a time and 5 then allowed to stand. After about 40 hours-the time is dependent on the acidity, concentration and temperature 0! the reaction mixture-the brown vanadate salts are converted to the blue vanadyl compounds indicating the completion of the oxidation.

The insoluble vanadium peritoxlde is removed by filtration, and the filtrate treated with small amounts or calcium ferrocyanide solution until the blue color oi the solution disappears. The 16 precipitated vanadium ferrocyanide compound is filtered, and the calcium ions in the filtrate are completely removed with oxalic acid. An analysis by Fehlings reduction method indicates a 50% yield of theory calculated as'z-ketc-gluconic acid.

The clear filtrate is then evaporated to dryness under diminished pressure. The residual sirup is taken up with about 200 cc. of methyl alcohol containing 20 grams of hydrochloric acid. This amount of hydrochloric acid precipitates the sodium ions as sodium chloride, whereupon the latter is subsequently filtered. The alcoholic solution now contains the tree organic acids in a concentration or about 1% hydrochloric acid to catalyze the esterifioation.

After about 24 hours standing the crystallized methyl z-keto-d-gluconate is recovered. Upon recrystallization from methyl alcohol it has a melting point of 174-175 C., and a specific rotation at equilibrimn []p=-'l6.8 (c=2.8) (Ohlc. Berichte 63:843-50, 1930). The recovered 2- keto-d-gluconic methyl ester is converted to isoascorblc acid by the method ofMaurer and Scheldt (Berichte, 67:1239-41, 1934). The pure recov-.- 4o ered isoascorbic acid has a melting point of 186 C., and its specific rotation is []n=-17.'7 (c=l0).

trample Z a The oxidation of sodium l-idonaie. to sodi z-keto-l-idonate. g

109 grams or sodium idonate, 18 grams sodium chlorate, 3 grams vanadium pentoxide, and 5 cc.

withsuilicientsolidbarhunfmnidetoprecream the vanadium and then filtered. zinc sulfate is added to the filtrate for the removal of ierrocyanide, phosphate and barium ions. The precipitate thus formed is filtered and washed; and the filtrate analyzed by Fehlings reduction method. The determination shows. the yield to be 60% of theory calculated as 2-keto-idonic acid. The clear filtrate is then concentrated under diminished pressure until it contains about 200 cc. of water. It is warmed to about 0., and 475 cc. of methyl alcohol is added to make the solution 70% by volume with respect to the alcohol. There is an immediate crystallization of -sodium 2-keto-l-idonate from this solution, which can be filtered at once. The dried sodium Z-ketol-idonate contains one molecule of water and is identical with sodium Z-keto-l-gulonate. The physical constants of the recovered salt agree with those reported by Mlcheel, Kraft 8: Lohmann (Z. Physiolog. Chemie 225:13-27, 1934) Its melting point is 144-145 C. and its specific rotation at equilibrium [a]D=-23.6 (c=l0).

' This sodium salt may be converted to ascorbic acid in the following manner. The calculated amount of sulfuric acid is added to a solution of this salt, and the solution evaporated to dryness under diminished pressure. The dry residue is diluted with methyl alcohol, and the insoluble sodium sulphate filtered. The alcoholic filtrate is treated with l%% of its weight of hydrochloric acid gas and refluxed at atmospheric pressure for 2 hours. Upon subsequent evaporation, the

-2-keto-l-idonic methyl ester crystallizes easily.

The recovered ester melts at 155-l56 C. (Reichstein and Griissner, Helv. Chim. Acta 17:311-28, 1934). 20 grams of this ester is suspended in cc. of'methyl alcohol .at 45 0., 5% over the theoretical amount of sodium methylate is added, and the mixture heated at 40-45" C. for 10 minutes. The massis then cooled and the calculated amount of sulfuric acid added. The insoluble sodium sulphate is filtered, and the filtrate evaporated. The concentrated solutions crystallized readily upon the addition of a few 1 crystals of ascorbic acid. The material obtained in this way has the known physical constants of l-ascorbic acid, melting point=189-191 C. and a specific rotation [u]n=+21 (c=l0).

Example III yield is 68% of theory calculated as 2-keto gulonic acid. The solutionyis then concentrated under diminished pressure to a volume of about 100 cc.

. It is warmed and subsequently diluted with physical and chemical properties are identical Example 2.

methyl alcohol to make the solution 70% with respect to the alcohol. 1 The sodium 2-keto-lgulonate dihydrate crystallizes immediately. fits with sodium'z-ke to-l-idon ate dihydrate given in area-m:

- acid Immplo I7 The oxidation of sodium d ldladtonll-te to sodium 2-keto-d-galactonate.

25.4 grams of sodimn gilactonate dihydrate is dissolved in 100 cc. of water and to thisis added 1 cc. of phosphoric acid 2 grams sodium diacid phosphate. 5 gram of vanadium pentoxide and 3.6 grams of sodium chlorate. The mixture is allowed to stand until a blue color appears in the solution. It is then filtered and the vanadyl ions removed as described in Examples 1 and 2. On analyzing by l'ehlings reduction method, the yield is 33% of theory calculated as Z-keto-galactonic acid. The extraneous ions are removed as outlined in Example 2.

The solution is concentrated and diluted with about one part of methyl alcohol and the solution is stirred. The crystalline material which is recovered is largely unreacted sodium galactonate. and this is, removed by filtration. The filtrate is evaporated under diminished pressure for the removal of the alcohol. The solution is analyzed for sodium and the calculated amount of sulphuricacid added to combine with the sodium. The chloride ions are then removed by the addition of silver oxide, and the silver chloride precipitate is filtered. The filtrate is then evaporated to dryness and taken up with alcohol, whence the insoluble sodium, sulphate is removed. The alcoholic filtrate 'is evaporated under diminished pressure to dryness, and the residual sirup is dissolved in water. The aqueous solution is neutralized with brucine. The solution is evaporated to dryness and taken up with a small amount of methyl alcohol. After about 48 hours standing crystallization takes place.

The recovered brucine salt was recrystallized three times from acetone. The final crystallization the specific rotation [a]n= -25.0 (c=l.2 water), and corresponds to brucine 2-keto-d-galactonate trihydrate CzaH:eO4N2.CsHmO-I+3H:O, as reported byKitasato '(Biochem. Z. 207:215-229, 4929). A small portion dried in vacuum at 60 C. has a melting point of (7., which is in agreement with that obtained by Kitasato on the anhydrous salt.

The invention claimed is:

1. Process for the preparation of z-keto-aldonic, acids by the action of a member of the group con-' sisting of alkali metal and alkaline earth metal chlorates upon a member of the group of aldonic acids and soluble aldonates in the presence of a vanadium catalyst and in a mildly acid 2. Process for the preparation of 2 -keto aldonates by the action of a member of the group consisting of alkali metal and alkaline earth metal chlorates upon soluble aldonates in the presence of vanadium as a catalyst and in a mildly acid med!- 3. Process for the preparation of 2-keto gluconates by theaction of a member of the group consisting of alkali metal and alkaline earth metal chlorates upon soluble gluconates in the presence of a catalyst and in a mildly acid medium. 4

4. Process for the preparation of 2-keto idonates, by the action of a member of the group consisting of alkali metal and alkaline earth metal chlorates upon soluble idonates in the presence of vanadium as a catalyst and in a mildly 5. Process foe-the preparation of 2-keto gulonate'sby the of a member of the'group is consisting of alkali metal and alkaline earth metal chlorates upon. soliilzule minutes in the presence oi vanadiumms a catalyst and in a mildly acid medium.

6. Process for the preparation 0! sodium 2- keto idonate by the action 01 sodium chlorate upon sodium idonate in the presence of vanadium asacatalystandinamildiy acidmedium.

7. Pxocess tor the preperetionoi fl-ketg eidonates by the notion of a. member of the group consisting of alkali metal and alkaline earth metal chlorates upon soluble aidonates'in the presence of vanadium as a catalyst and a. sumeient quantity otbu'i'ter to maintain the pH be- 5 tween 3 and.

' RICHARD PAB'I'ERNACK.

I PETER P. REGNA. 

